Age-related macular degeneration is a disease that causes abnormality in the macula of the retina; it is the leading cause of vision loss in Europe and the United States. In Japan, the disease is also steadily increasing because of the aging population. The macula is located in the center of the retina, and the region is densely populated with cone cells among the photoreceptor cells. Rays of light coming from outside are refracted by the cornea and crystalline lens, and then converge on the macula, the central fovea in particular. The ability to read letters depends on the function of this area. In age-related macular degeneration, the macula, which is an important area as described above, degenerates with age and results in visual impairment, mainly in the form of image distortion (anorthopia) and central scotoma.
The wet form of age-related macular degeneration is a disease with a poor prognosis, which results in rapid and severe visual impairment. The major pathological condition is choroidal neovascularization (herein below, sometimes abbreviated as “CNV”). CNV refers to ectopic growth of choroidal vessels, penetrating through Bruch's membrane and retinal pigment epithelia. In wet age-related macular degeneration, hemorrhage and leakage of plasma components comprising fat from the premature vascular plexus is the direct cause of the rapid functional impairment of the neural retina. CNV is thought to be induced by inflammatory cells mainly comprising macrophages that infiltrate to phagocytose drusen accumulated at the subretinal macular area. Inflammatory cells such as macrophages are also sources of production of angiogenic factors, such as vascular endothelial growth factor (VEGF), and they function to enhance neovascularization at sites of inflammation. This process is called “inflammatory neovascularization”. Meanwhile, drusen comprise advanced glycation end-products (AGE) and amyloid β, which are substances that stimulate VEGF production; these substances stimulate retinal pigment epithelia that have migrated to engulf drusen, resulting in VEGF secretion, and this is thought to be another possible mechanism by which CNV develops.
Diseases involving CNV include myopic choroidal neovascularization and idiopathic choroidal neovascularization as well as age-related macular degeneration. Development of diseases involving CNV can sometimes be ascribed to angioid streaks, injury, uveitis, or such. Tissue damage mainly of the Bruch's membrane and retinal pigment epithelia in the subretinal macular area, and the subsequent inflammation, have been suggested to be involved in the mechanism of CNV onset in these diseases, as well as in age-related macular degeneration.
Recent studies demonstrated that VEGF produced in association with inflammation was involved in CNV. Diseases involving CNV have been treated using VEGF antagonists, such as anti-VEGF aptamers, with some degree of success. VEGF antagonists are administered at an advanced stage, when neovascularization develops; however, this is problematic in that irreversible and incurable neurologic damage will remain when therapies begin after entering this advanced stage.
IL-6 is a cytokine called B-cell stimulating factor 2 (BSF2) or interferon β2. IL-6 was discovered as a differentiation factor involved in the activation of B-cell lymphocytes (Non-patent Document 1), and was later revealed to be a multifunctional cytokine that influences the function of various cells (Non-patent Document 2). IL-6 has been reported to induce maturation of T lymphocyte cells (Non-patent Document 3).
IL-6 transmits its biological activity via two kinds of proteins on the cell. The first kind of protein is the IL-6 receptor, which is a ligand binding protein to which IL-6 binds; it has a molecular weight of about 80 kDa (Non-patent Documents 4 to 5). The IL-6 receptor is present in a membrane-bound form that penetrates and is expressed on the cell membrane, and also as a soluble IL-6 receptor, which mainly consists of the extracellular region of the membrane-bound form.
The other kind of protein is the membrane protein gp 130, which has a molecular weight of about 130 kDa and is involved in non-ligand binding signal transduction. The biological activity of IL-6 is transmitted into the cell through formation of an IL-6/IL-6 receptor complex by IL-6 and IL-6 receptor followed by binding of the complex with gp130 (Non-patent Document 6).
IL-6 inhibitors are substances that inhibit the transmission of IL-6 biological activity. Currently, known IL-6 inhibitors include antibodies against IL-6 (anti-IL-6 antibodies), antibodies against IL-6 receptor (anti-IL-6 receptor antibodies), antibodies against gp130 (anti-gp130 antibodies), IL-6 variants, partial peptides of IL-6 or IL-6 receptor, and such.
There are several reports regarding anti-IL-6 receptor antibodies (Non-patent Documents 7 to 8 and Patent Documents 1 to 3). One such report details a humanized PM-1 antibody, which is obtained by transplanting the complementarity determining region (CDR) of mouse antibody PM-1 (Non-patent Document 9), which is an anti-IL-6 receptor antibody, into a human antibody (Patent Document 4).
The level of inflammatory cytokine IL-6 in patients with age-related macular degeneration has recently been reported to be elevated (Non-patent Document 10). However, the role of IL-6 in diseases involving CNV remains to be clarified.
Prior art literature relating to the present invention of this application is shown below.    Patent Document 1: International Patent Application Publication No. WO 95/09873    Patent Document 2: French Patent Application No. FR 2694767    Patent Document 3: U.S. Pat. No. 5,216,128    Patent Document 4: International Patent Application Publication No. WO 92/19759    Non-patent Document 1: Hirano, T. et al., Nature (1986) 324, 73-76    Non-patent Document 2: Akira, S. et al., Adv. in Immunology (1993) 54, 1-78    Non-patent Document 3: Lotz, M. et al., J. Exp. Med. (1988) 167, 1253-1258    Non-patent Document 4: Taga, T. et al., J. Exp. Med. (1987) 166, 967-981    Non-patent Document 5: Yamasaki, K. et al., Science (1988) 241, 825-828    Non-patent Document 6: Taga, T. et al., Cell (1989) 58, 573-581    Non-patent Document 7: Novick, D. et al., Hybridoma (1991) 10, 137-146    Non-patent Document 8: Huang, Y W. et al., Hybridoma (1993) 12, 621-630    Non-patent Document 9: Hirata, Y. et al., J. Immunol. (1989) 143, 2900-2906    Non-patent Document 10: Seddon J. M., Arch Opthalmol. 2005 Jun, 123(6), 774-82